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Alessandra: Cytochrome p450: Biosynthesis
Cytochrome P450 family 3 subfamily A peptide 4 This gene encodes a member of the cytochrome p450 family. These proteins catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steriods, and other lipids. This proteins expression is induced by glucocorticoids, and are localized to the enodplasmic reticulum. The gene is part of a cluster of cytochrome p450 genes on chromosome 7q21.1. CYP3A4 in humans Cytochrome P450 3A4 is the dominant metabolizing CYP. CYP3A4 is synthesized and active in human liver microsomes. CYP3A4 catalysis occurs often because of allosteric activation in the liver (Woods ''et al. 2011). The CYP enzymes catalyze the oxidation of xenobiotics, a foreign chemical substance, and drugs in the body, primarily due to its high expression levels in the liver and the small intestine. Cytochrome p450 proteins are found in both soluble and membrane- bound forms. One of the key aspects of their function is the mechanism and pathway by which various molecules gain access to the active site of the enzyme. This process is particularly important for membrane associated CYPs. Human CYPs are anchored in the cellular membrane by an N-terminal transmembrane α helix. Over 1000 compounds have been identified that interact with and affect the activity of CYP3A4 in the membrane. In order to fully understand CYP3A4, it is important to understand the interactions with the membrane. Cytochrome p450 3A4 first encounters the cellular membrane at the hydrophobic helices F’ and G’ with a hydrophobic anchor composed of residues Leu- 44, Pro- 45, Phe- 46 and Leu- 47. This interaction can be seen with the image to the right '(Baylon et al. ''2013)'.This anchor, located between helices A” and A is called the “A- anchor” and is one of the distinguishing features of CYP3A4. This “A- anchor” binding to the membrane allows the opening of access tunnels to the active site of the protein that are not observed in crystal structures. In particular, rearrangement of the Phe- 46 cluster on the anchor is one of the major structural changes that causes the opening of tunnels so that the active site can be more easily accessed. Pages #Alessandra: Cytochrome p450: Introduction #Alessandra: Cytochrome p450: Biological function #Alessandra: Cytochrome p450: Biosynthesis #Alessandra: Cytochrome p450: Gene sequence #Alessandra: Cytochrome p450: Amino acid sequence and composition #Alessandra: Cytochrome p450: Secondary and tertiary structure #Alessandra: Cytochrome p450: Domains and structural motifs #Alessandra: Cytochrome p450: Interactions with macromolecules and small molecules #Alessandra: Cytochrome p450: Molecular biodiversity and evolution #Alessandra: Cytochrome p450: Literature overview #Alessandra: Cytochrome p450: Useful online resources References Baylon, Javier J., Ivan L. Lenov, Stephen G. Silgar, and Emad Tajkhorshid. "Characterizing the Membrane-Bound State of Cytochrome P450 3A4: Structure, Depth of Insertion, and Orientation. " Journal of the American Chemical Society 135.23 (2013): 8542-551. NCBI. Web. 18 Feb. 2014. CYP3A4 Wikipedia Article Woods, Caleb M., Christina Fernandez, Kent L. Kunze, and William M. Atkins. “Allosteric Activation of Cytochrome P450 3A4 by α- Naphthoflavone: Branch Point Regulation Revealed by Isotope Dilution Analysis. ” Biochemistry 50.46 (2011): 41-51. NCBI. Web. 18 Feb. 2014.